The isolation of .beta.-endorphin from mammalian brain and pituitary extracts has been described in the art. See for example U.S. Pat. No. 4,038,222 reissued as U.S. Pat. No. RE 29,842. The availability of synthetic methods for preparing .beta.-endorphin has allowed studies into structure-activity relationship with analogs of .beta.-endorphin.
Modifications have been made in the amino terminal or enkephalin portion of the molecule, i.e., (1-5) .beta.-endorphin. Similar modifications made in enkephalin had produced enkephalin analogs with substantially enhanced analgesic activity over that of the parent compound. However, the .beta.-endorphin analogs with few exceptions such as, for example [D-Ala.sup.2 ]-.beta.-endorphin, did not have the level of activity of the parent compound. See in this regard Yamashiro et al., Int. J. Pept. Prot. Res. 10, 159 (1977). Analogs which are modified in both the amino and carboxy terminal sequences are described in U.S. Pat. No. 4,116,950. Again all compounds which have modifications in the enkephalin region (1-5) exhibit reduced analgesic potency compared to .beta.-endorphin.
Thus as seen above efforts to increase the analgesic potency of .beta.-endorphin by entrapolating findings on enkephalin analogs to the .beta.-endorphin case have generally not been successful. Note also Li in Hormonal Proteins and Peptides X pp. 1-34 (Academic Press, New York 1981). The most potent enkephalin analogs have resulted from changes in both positions 2 and 5. As an example, [D-Ala.sup.2, D-Leu.sup.5 ]-enkephalin has been reported to be almost equipotent with .beta..sub.c -endorphin as an analgesic. See Wei et al., Life Sci. 21 321 (1977). However, [D-Ala.sup.2, D-Leu.sup.5 ]-.beta..sub.h -endorphin has only 8% of the activity of .beta..sub.h -endorphin as reported by Yamashiro et al. Int. J. Pep. Prot. Res. 11, 251 (1978).
It has recently been reported that dermorphin, a heptapeptide of the sequence H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH.sub.2, isolated from the skin of the South American frog Phyllomedusa sauvege has potent analgesic properties. See Montecucchi et al. Int. J. Pep. Prot. Res. 17, 275 (1981). Broccardo et al. Br. J. Pharmacol. 73, 625 (1981) have reported that dermorphin is 752 times more active than morphine in a rat tail-flick assay. For comparison camel .beta.-endorphin is about 33 times more active than morphine in the same assay as reported by Lok et al., Proc. Natl. Acad. Sci. USA 73, 2895 (1976).